Journal articles: 'HIV (Viruses) – Treatment – Namibia'

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Schellekens, Onno P., Ingrid de Beer, Marianne E. Lindner, Michele van Vugt, Peter Schellekens, and Tobias F. Rinke de Wit. "Innovation In Namibia: Preserving Private Health Insurance And HIV/AIDS Treatment." Health Affairs 28, no. 6 (November 2009): 1799–806. http://dx.doi.org/10.1377/hlthaff.28.6.1799.

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Low, Andrea, Karam Sachathep, George Rutherford, Anne-Marie Nitschke, Adam Wolkon, Karen Banda, Leigh Ann Miller, et al. "Migration in Namibia and its association with HIV acquisition and treatment outcomes." PLOS ONE 16, no. 9 (September 2, 2021): e0256865. http://dx.doi.org/10.1371/journal.pone.0256865.

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Background In the 21st century, understanding how population migration impacts human health is critical. Namibia has high migration rates and HIV prevalence, but little is known about how these intersect. We examined the association between migration and HIV-related outcomes using data from the 2017 Namibia Population-based HIV Impact Assessment (NAMPHIA). Methods and findings The NAMPHIA survey selected a nationally representative sample of adults in 2017. All adults aged 15–64 years were invited to complete an interview and home-based HIV test. Recent infection (<130 days) was measured using HIV-1 LAg avidity combined with viral load (>1000 copies/mL) and antiretroviral analyte data. Awareness of HIV status and antiretroviral use were based on self-report and/or detectable antiretrovirals in blood. Viremia was defined as having a viral load ≥1000 copies/mL, including all participants in the denominator regardless of serostatus. We generated community viremia values as a weighted proportion at the EA level, excluding those classified as recently infected. Significant migrants were those who had lived outside their current region or away from home >one month in the past three years. Recent cross-community in-migrants were those who had moved to the community <two years ago. Separate analyses were done to compare significant migrants to non-migrants and recent cross-community in-migrants to those who in-migrated >two years ago to determine the association of migration and timing with recent infection or viral load suppression (VLS). All proportions are weighted. Of eligible adults, we had HIV results and migration data on 9,625 (83.9%) of 11,474 women and 7,291 (73.0%) of 9,990 men. Most respondents (62.5%) reported significant migration. Of cross-community in-migrants, 15.3% were recent. HIV prevalence was 12.6% and did not differ by migration status. Population VLS was 77.4%. Recent cross-community in-migration was associated with recent HIV infection (aOR: 4.01, 95% CI 0.99–16.22) after adjusting for community viremia. Significant migration (aOR 0.73, 95% CI: 0.55–0.97) and recent cross-community in-migration (aOR 0.57, 95% CI: 0.35–0.92) were associated with lower VLS, primarily due to lack of awareness of HIV infection. The study was limited by lack of precise data on trajectory of migration. Conclusions Despite a high population-level VLS, Namibia still has migrant populations that are not accessing effective treatment for HIV. Targeting migrants with effective prevention and testing programs in communities with viremia could enable further epidemic control.

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Hong, Steven Y., Laimi S. N. Ashipala, Leonard Bikinesi, Ndapewa Hamunime, Jacques W. N. Kamangu, Ashley Boylan, Edwin Sithole, et al. "Rapid Adaptation of HIV Treatment Programs in Response to COVID-19 — Namibia, 2020." MMWR. Morbidity and Mortality Weekly Report 69, no. 42 (October 23, 2020): 1549–51. http://dx.doi.org/10.15585/mmwr.mm6942a6.

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Baxen, Jean, and Emilie Haipinge. "School experiences of HIV-positive secondary school learners on ARV treatment in Namibia." International Journal of Educational Development 41 (March 2015): 237–44. http://dx.doi.org/10.1016/j.ijedudev.2014.11.002.

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Kidder, Daniel P., Pam Bachanas, Amy Medley, Sherri Pals, Harriet Nuwagaba-Biribonwoha, Marta Ackers, Andrea Howard, et al. "HIV Prevention in Care and Treatment Settings: Baseline Risk Behaviors among HIV Patients in Kenya, Namibia, and Tanzania." PLoS ONE 8, no. 2 (February 25, 2013): e57215. http://dx.doi.org/10.1371/journal.pone.0057215.

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Seeling, Stefanie, Farai Mavhunga, Albertina Thomas, Bettina Adelberger, and Timo Ulrichs. "Barriers to access to antiretroviral treatment for HIV-positive tuberculosis patients in Windhoek, Namibia." International Journal of Mycobacteriology 3, no. 4 (December 2014): 268–75. http://dx.doi.org/10.1016/j.ijmyco.2014.07.009.

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Andrade, Viviane M., Carla Mavian, Dunja Babic, Thaissa Cordeiro, Mark Sharkey, Labelle Barrios, Christian Brander, et al. "A minor population of macrophage-tropic HIV-1 variants is identified in recrudescing viremia following analytic treatment interruption." Proceedings of the National Academy of Sciences 117, no. 18 (April 16, 2020): 9981–90. http://dx.doi.org/10.1073/pnas.1917034117.

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HIV-1 persists in cellular reservoirs that can reignite viremia if antiretroviral therapy (ART) is interrupted. Therefore, insight into the nature of those reservoirs may be revealed from the composition of recrudescing viremia following treatment cessation. A minor population of macrophage-tropic (M-tropic) viruses was identified in a library of recombinant viruses constructed with individual envelope genes that were obtained from plasma of six individuals undergoing analytic treatment interruption (ATI). M-tropic viruses could also be enriched from post-ATI plasma using macrophage-specific (CD14) but not CD4+ T cell-specific (CD3) antibodies, suggesting that M-tropic viruses had a macrophage origin. Molecular clock analysis indicated that the establishment of M-tropic HIV-1 variants predated ATI. Collectively, these data suggest that macrophages are a viral reservoir in HIV-1–infected individuals on effective ART and that M-tropic variants can appear in rebounding viremia when treatment is interrupted. These findings have implications for the design of curative strategies for HIV-1.

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Fletcher, Courtney V. "Treatment of Herpesvirus Infections in Hiv-Infected Individuals." Annals of Pharmacotherapy 26, no. 7-8 (July 1992): 955–62. http://dx.doi.org/10.1177/106002809202600720.

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OBJECTIVE: To discuss strategies available for the treatment of herpesvirus infections in individuals infected with HIV. DATA SOURCES: Information was obtained from controlled and uncontrolled clinical trials, abstracts, conference proceedings, and review articles. STUDY SELECTION: Emphasis was placed on controlled investigations in subjects infected with HIV. DATA EXTRACTION: Data from human studies were extracted by the author and evaluated according to the patient population studied, sample size, dosage regimen, and therapeutic response. DATA SYNTHESIS: Herpes group viruses are common opportunistic pathogens in HIV-infected individuals. Zoster, caused by varicella-zoster virus (VZV), is an early indication of the loss of cell-mediated immunity and HIV disease progression. Anorectal mucocutaneous disease is the most common manifestation caused by herpes simplex virus (HSV). Acyclovir is the drug of choice for treatment of both VZV and HSV infections. Cytomegalovirus (CMV) is the most common life-threatening viral infection in patients with AIDS; retinitis is the most frequent clinical manifestation. The response rate of CMV retinitis to initial treatment with either ganciclovir or foscarnet is equivalent, approximately 60–90 percent. Recent data suggest that the survival benefit may be greater with foscarnet. CONCLUSIONS: Advances in the development and application of antiviral drugs for herpes group viruses have made treatment and, in some cases, prevention of infections possible. Future efforts, aimed at earlier intervention and suppression of latent virus, may offer additional improvement in quality of life for the HIV-infected individual.

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Lu, Ching-Lan, Joy A. Pai, Lilian Nogueira, Pilar Mendoza, Henning Gruell, Thiago Y. Oliveira, John Barton, et al. "Relationship between intact HIV-1 proviruses in circulating CD4+ T cells and rebound viruses emerging during treatment interruption." Proceedings of the National Academy of Sciences 115, no. 48 (November 12, 2018): E11341—E11348. http://dx.doi.org/10.1073/pnas.1813512115.

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Combination antiretroviral therapy controls but does not cure HIV-1 infection because a small fraction of cells harbor latent viruses that can produce rebound viremia when therapy is interrupted. The circulating latent virus reservoir has been documented by a variety of methods, most prominently by viral outgrowth assays (VOAs) in which CD4+ T cells are activated to produce virus in vitro, or more recently by amplifying proviral near full-length (NFL) sequences from DNA. Analysis of samples obtained in clinical studies in which individuals underwent analytical treatment interruption (ATI), showed little if any overlap between circulating latent viruses obtained from outgrowth cultures and rebound viruses from plasma. To determine whether intact proviruses amplified from DNA are more closely related to rebound viruses than those obtained from VOAs, we assayed 12 individuals who underwent ATI after infusion of a combination of two monoclonal anti–HIV-1 antibodies. A total of 435 intact proviruses obtained by NFL sequencing were compared with 650 latent viruses from VOAs and 246 plasma rebound viruses. Although, intact NFL and outgrowth culture sequences showed similar levels of stability and diversity with 39% overlap, the size of the reservoir estimated from NFL sequencing was larger than and did not correlate with VOAs. Finally, intact proviruses documented by NFL sequencing showed no sequence overlap with rebound viruses; however, they appear to contribute to recombinant viruses found in plasma during rebound.

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Goh, Gerard, A. Dunker, James Foster, and Vladimir Uversky. "HIV Vaccine Mystery and Viral Shell Disorder." Biomolecules 9, no. 5 (May 8, 2019): 178. http://dx.doi.org/10.3390/biom9050178.

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Hundreds of billions of dollars have been spent for over three decades in the search for an effective human immunodeficiency virus (HIV) vaccine with no success. There are also at least two other sexually transmitted viruses, for which no vaccine is available, the herpes simplex virus (HSV) and the hepatitis C virus (HCV). Traditional textbook explanatory paradigm of rapid mutation of retroviruses cannot adequately address the unavailability of vaccine for many sexually transmissible viruses, since HSV and HCV are DNA and non-retroviral RNA viruses, respectively, whereas effective vaccine for the horsefly-transmitted retroviral cousin of HIV, equine infectious anemia virus (EIAV), was found in 1973. We reported earlier the highly disordered nature of proteins in outer shells of the HIV, HCV, and HSV. Such levels of disorder are completely absent among the classical viruses, such as smallpox, rabies, yellow fever, and polio viruses, for which efficient vaccines were discovered. This review analyzes the physiology and shell disorder of the various related and non-related viruses to argue that EIAV and the classical viruses need harder shells to survive during harsher conditions of non-sexual transmissions, thus making them vulnerable to antibody detection and neutralization. In contrast, the outer shell of the HIV-1 (with its preferential sexual transmission) is highly disordered, thereby allowing large scale motions of its surface glycoproteins and making it difficult for antibodies to bind to them. The theoretical underpinning of this concept is retrospectively traced to a classical 1920s experiment by the legendary scientist, Oswald Avery. This concept of viral shapeshifting has implications for improved treatment of cancer and infections via immune evasion.

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Mills, J. S. "Virus Proteinase Inhibitors — What Next after HIV?" Antiviral Chemistry and Chemotherapy 7, no. 6 (December 1996): 281–93. http://dx.doi.org/10.1177/095632029600700601.

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The recent approval by the regulatory authorities in the United States of several HIV proteinase inhibitors as therapeutics for the treatment of AIDS confirms that virus proteinases are valid molecular targets in the search for new antiviral drugs. This review summarizes the available approaches that can be taken to discover virus proteinase inhibitors and reviews the current status of our knowledge with respect to virus proteinases in viruses of clinical significance other than HIV. The major focus is on proteinases identified in the viruses that cause the common cold, hepatitis C virus and the herpesviruses.

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Vigerust, David. "Protein glycosylation in infectious disease pathobiology and treatment." Open Life Sciences 6, no. 5 (October 1, 2011): 802–16. http://dx.doi.org/10.2478/s11535-011-0050-8.

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AbstractA host of bacteria and viruses are dependent on O-linked and N-linked glycosylation to perform vital biological functions. Pathogens often have integral proteins that participate in host-cell interactions such as receptor binding and fusion with host membrane. Fusion proteins from a broad range of disparate viruses, such as paramyxovirus, HIV, ebola, and the influenza viruses share a variety of common features that are augmented by glycosylation. Each of these viruses contain multiple glycosylation sites that must be processed and modified by the host post-translational machinery to be fusogenically active. In most viruses, glycosylation plays a role in biogenesis, stability, antigenicity and infectivity. In bacteria, glycosylation events play an important role in the formation of flagellin and pili and are vitally important to adherence, attachment, infectivity and immune evasion. With the importance of glycosylation to pathogen survival, it is clear that a better understanding of the processes is needed to understand the pathogen requirement for glycosylation and to capitalize on this requirement for the development of novel therapeutics.

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Spector, S. A., K. Hsia, F. Denaro, and D. H. Spector. "Use of molecular probes to detect human cytomegalovirus and human immunodeficiency virus." Clinical Chemistry 35, no. 8 (August 1, 1989): 1581–87. http://dx.doi.org/10.1093/clinchem/35.8.1581.

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Abstract Human cytomegalovirus (HCMV) and human immunodeficiency virus (HIV) cause severe disease. The identification of these viruses in clinical specimens and understanding the progression of infection and diseases relating to HCMV and HIV are essential to develop effective means for treatment and prevention. Here we describe the application of molecular probes to the diagnosis and pathogenesis of HCMV and HIV. In situ hybridization and the amplification procedure of polymerase chain reaction are used to detect both viruses; these techniques have provided important information regarding the pathogenesis of HCMV and HIV. A new technique, target cycling, may also prove useful for the detection of viruses by enriching for target sequences. The continued application of molecular probes to pathogenetic studies of HCMV and HIV promises to further our knowledge of these viruses, and of their interaction.

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Lisovsky, Irene, Susan M. Schader, Jorge-Luis Martinez-Cajas, Maureen Oliveira, Daniela Moisi, and Mark A. Wainberg. "HIV-1 Protease Codon 36 Polymorphisms and Differential Development of Resistance to Nelfinavir, Lopinavir, and Atazanavir in Different HIV-1 Subtypes." Antimicrobial Agents and Chemotherapy 54, no. 7 (April 19, 2010): 2878–85. http://dx.doi.org/10.1128/aac.01828-09.

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ABSTRACT The amino acid at position 36 of the HIV-1 protease differs among various viral subtypes, in that methionine is usually found in subtype B viruses but isoleucine is common in other subtypes. This polymorphism is associated with higher rates of treatment failure involving protease inhibitors (PIs) in non-subtype B-infected patients. To investigate this, we generated genetically homogeneous wild-type viruses from subtype B, subtype C, and CRF02_AG full-length molecular clones and showed that subtype C and CRF02_AG I36 viruses exhibited higher levels of resistance to various PIs than their respective M36 counterparts, while the opposite was observed for subtype B viruses. Selections for resistance with each variant were performed with nelfinavir (NFV), lopinavir (LPV), and atazanavir (ATV). Sequence analysis of the protease gene at week 35 revealed that the major NFV resistance mutation D30N emerged in NFV-selected subtype B viruses and in I36 subtype C viruses, despite polymorphic variation. A unique mutational pattern developed in subtype C M36 viruses selected with NFV or ATV. The presence of I47A in LPV-selected I36 CRF02_AG virus conferred higher-level resistance than L76V in LPV-selected M36 CRF02_AG virus. Phenotypic analysis revealed a >1,000-fold increase in NFV resistance in I36 subtype C NFV-selected virus with no apparent impact on viral replication capacity. Thus, the position 36 polymorphism in the HIV-1 protease appears to have a differential effect on both drug susceptibility and the viral replication capacity, depending on both the viral subtype and the drug being evaluated.

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Maggiolo, Franco, Annapaola Callegaro, Giampietro Gregis, Giampaolo Quinzan, Diego Ripamonti, Claudio Arici, Antonio Goglio, and Fredy Suter. "Strategic selective treatment in highly pre-treated HIV patients harbouring multiply resistant viruses." AIDS 16, no. 2 (January 2002): 298–99. http://dx.doi.org/10.1097/00002030-200201250-00024.

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Agabu, Andrew, Andrew L. Baughman, Christa Fischer-Walker, Michael de Klerk, Nicholus Mutenda, Francina Rusberg, Dorothea Diergaardt, et al. "National-level effectiveness of ART to prevent early mother to child transmission of HIV in Namibia." PLOS ONE 15, no. 11 (November 10, 2020): e0233341. http://dx.doi.org/10.1371/journal.pone.0233341.

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Background Namibia introduced the prevention of mother to child HIV transmission (MTCT) program in 2002 and lifelong antiretroviral therapy (ART) for pregnant women (option B-plus) in 2013. We sought to quantify MTCT measured at 4–12 weeks post-delivery. Methods During Aug 2014-Feb 2015, we recruited a nationally representative sample of 1040 pairs of mother and infant aged 4–12 weeks at routine immunizations in 60 public health clinics using two stage sampling approach. Of these, 864 HIV exposed infants had DNA-PCR HIV test results available. We defined an HIV exposed infant if born to an HIV-positive mother with documented status or diagnosed at enrollment using rapid HIV tests. Dried Blood Spots samples from HIV exposed infants were tested for HIV. Interview data and laboratory results were collected on smartphones and uploaded to a central database. We measured MTCT prevalence at 4–12 weeks post-delivery and evaluated associations between infant HIV infection and maternal and infant characteristics including maternal treatment and infant prophylaxis. All statistical analyses accounted for the survey design. Results Based on the 864 HIV exposed infants with test results available, nationally weighted early MTCT measured at 4–12 weeks post-delivery was 1.74% (95% confidence interval (CI): 1.00%-3.01%). Overall, 62% of mothers started ART pre-conception, 33.6% during pregnancy, 1.2% post-delivery and 3.2% never received ART. Mothers who started ART before pregnancy and during pregnancy had low MTCT prevalence, 0.78% (95% CI: 0.31%-1.96%) and 0.98% (95% CI: 0.33%-2.91%), respectively. MTCT rose to 4.13% (95% CI: 0.54%-25.68%) when the mother started ART after delivery and to 11.62% (95% CI: 4.07%-28.96%) when she never received ART. The lowest MTCT of 0.76% (95% CI: 0.36% - 1.61%) was achieved when mother received ART and ARV prophylaxis within 72hrs for infant and highest 22.32% (95%CI: 2.78% -74.25%) when neither mother nor infant received ARVs. After adjusting for mother’s age, maternal ART (Prevalence Ratio (PR) = 0.10, 95% CI: 0.03–0.29) and infant ARV prophylaxis (PR = 0.32, 95% CI: 0.10–0.998) remained strong predictors of HIV transmission. Conclusion As of 2015, Namibia achieved MTCT of 1.74%, measured at 4–12 weeks post-delivery. Women already on ART pre-conception had the lowest prevalence of MTCT emphasizing the importance of early HIV diagnosis and treatment initiation before pregnancy. Studies are needed to measure MTCT and maternal HIV seroconversion during breastfeeding.

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Vu, Lung, Brady Burnett-Zieman, Lizl Stoman, Minh Luu, Johnface Mdala, Krista Granger, Steven Forsythe, Abeje Zegeye, and Scott Geibel. "Effects of the implementation of the HIV Treat All guidelines on key ART treatment outcomes in Namibia." PLOS ONE 15, no. 12 (December 28, 2020): e0243749. http://dx.doi.org/10.1371/journal.pone.0243749.

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Background This study aimed to help the Namibian government understand the impact of Treat All implementation (started on April 1, 2017) on key antiretroviral therapy (ART) outcomes, and how this transition impacts progress toward the UNAIDS’s 90-90-90 HIV targets. Methods We collected clinical records from two separate cohorts (before and after treat-all) of ART patients in 10 high- and medium-volume facilities in 6 northern Namibia districts. Each cohort contains 12-month data on patients’ scheduled appointments and visits, health status, and viral load results. We also measured patients’ wait time and perceptions of service quality using exit interviews with 300 randomly selected patients (per round). We compared ART outcomes of the two cohorts: ART initiation within 7 days from diagnosis, loss to follow-up (LTFU), missed scheduled appointments for at least 30 days, and viral suppression using unadjusted and adjusted analyses. Results Among new ART clients (on ART for less than 3 months or had not yet initiated treatment as of the start date for the ART record review period), rapid ART initiation (within 7 days from diagnosis) was 5.2 times higher after Treat All than that among clients assessed before the policy took effect [AOR: 5.2 (3.8–6.9)]. However, LTFU was higher after Treat All roll-out compared to before Treat All [AOR: 1.9 (1.3–2.8)]. Established ART clients (on ART treatment for at least three months at the start date of the ART record review period) had over 3 times greater odds of achieving viral suppression after Treat All roll-out compared to established ART clients assessed before Treat All [AOR: 3.1 (1.6–5.9)]. Conclusions and recommendations The findings indicate positive effect of the “Treat All” implementation on ART initiation and viral suppression, and negative effect on LTFU. Additionally, by April 2018, Namibia seems to have reached the UNAIDS’s 90-90-90 targets.

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Bobkova, M. R. "Genetic diversity of human immunodeficiency viruses and antiretroviral therapy." Terapevticheskii arkhiv 88, no. 11 (November 15, 2016): 103–11. http://dx.doi.org/10.17116/terarkh20168811103-111.

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The lecture is devoted to the analysis of the state-of-the-art of the impact of genetic diversity of human immunodeficiency (HIV) viruses on the pattern of infection and the efficiency of antiretroviral therapy (ART). It provides brief information on the origin and evolution of HIV and on the current classification of their genetic variants. The molecular epidemiological situation of HIV infection in Russia and nearby states and the major molecular HIV variants that are dominant in these countries, as well as their origin and prevalence trends are characterized. How the diversity of HIV can affect the efficiency of diagnosis, the transmission of the virus, and the pattern of HIV pathogenesis are briefly reviewed. The comparative data available in the world’s scientific literature on these topics are given. More detailed attention is given to the possible causes of varying therapeutic effects against different HIV subtypes, as well as to the specific features of the formation and phenotyping manifestation of ART drug resistance mutations. There is evidence for the necessity of forming a unified follow-up system for treated HIV-infected patients during ART scaling, including in an effort to evaluate the impact of the specific features of the HIV genome on the efficiency of treatment regimens used in Russia.

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Cohen, Yehuda Z., Julio C. C. Lorenzi, Lisa Krassnig, John P. Barton, Leah Burke, Joy Pai, Ching-Lan Lu, et al. "Relationship between latent and rebound viruses in a clinical trial of anti–HIV-1 antibody 3BNC117." Journal of Experimental Medicine 215, no. 9 (August 2, 2018): 2311–24. http://dx.doi.org/10.1084/jem.20180936.

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A clinical trial was performed to evaluate 3BNC117, a potent anti–HIV-1 antibody, in infected individuals during suppressive antiretroviral therapy and subsequent analytical treatment interruption (ATI). The circulating reservoir was evaluated by quantitative and qualitative viral outgrowth assay (Q2VOA) at entry and after 6 mo. There were no significant quantitative changes in the size of the reservoir before ATI, and the composition of circulating reservoir clones varied in a manner that did not correlate with 3BNC117 sensitivity. 3BNC117 binding site amino acid variants found in rebound viruses preexisted in the latent reservoir. However, only 3 of 217 rebound viruses were identical to 868 latent viruses isolated by Q2VOA and near full-length sequencing. Instead, 63% of the rebound viruses appeared to be recombinants, even in individuals with 3BNC117-resistant reservoir viruses. In conclusion, viruses emerging during ATI in individuals treated with 3BNC117 are not the dominant species found in the circulating latent reservoir, but frequently appear to represent recombinants of latent viruses.

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Bertagnolli, Lynn N., Joseph Varriale, Sarah Sweet, Jacqueline Brockhurst, Francesco R. Simonetti, Jennifer White, Subul Beg, et al. "Autologous IgG antibodies block outgrowth of a substantial but variable fraction of viruses in the latent reservoir for HIV-1." Proceedings of the National Academy of Sciences 117, no. 50 (November 25, 2020): 32066–77. http://dx.doi.org/10.1073/pnas.2020617117.

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In untreated HIV-1 infection, rapid viral evolution allows escape from immune responses. Viral replication can be blocked by antiretroviral therapy. However, HIV-1 persists in a latent reservoir in resting CD4+ T cells, and rebound viremia occurs following treatment interruption. The reservoir, which is maintained in part by clonal expansion, can be measured using quantitative viral outgrowth assays (QVOAs) in which latency is reversed with T cell activation to allow viral outgrowth. Recent studies have shown that viruses detected in QVOAs prior to treatment interruption often differ from rebound viruses. We hypothesized that autologous neutralizing antibodies directed at the HIV-1 envelope (Env) protein might block outgrowth of some reservoir viruses. We modified the QVOA to reflect pressure from low concentrations of autologous antibodies and showed that outgrowth of a substantial but variable fraction of reservoir viruses is blocked by autologous contemporaneous immunoglobulin G (IgG). A reduction in outgrowth of >80% was seen in 6 of 15 individuals. This effect was due to direct neutralization. We established a phylogenetic relationship between rebound viruses and viruses growing out in vitro in the presence of autologous antibodies. Some large infected cell clones detected by QVOA carried neutralization-sensitive viruses, providing a cogent explanation for differences between rebound virus and viruses detected in standard QVOAs. Measurement of the frequency of reservoir viruses capable of outgrowth in the presence of autologous IgG might allow more accurate prediction of time to viral rebound. Ultimately, therapeutic immunization targeting the subset of variants resistant to autologous IgG might contribute to a functional cure.

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Cilliers, Tonie, Jabulani Nhlapo, Mia Coetzer, Dragana Orlovic, Thomas Ketas, William C. Olson, John P. Moore, Alexandra Trkola, and Lynn Morris. "The CCR5 and CXCR4 Coreceptors Are Both Used by Human Immunodeficiency Virus Type 1 Primary Isolates from Subtype C." Journal of Virology 77, no. 7 (April 1, 2003): 4449–56. http://dx.doi.org/10.1128/jvi.77.7.4449-4456.2003.

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ABSTRACT Human immunodeficiency virus type 1 (HIV-1) subtype C viruses with different coreceptor usage profiles were isolated from 29 South African patients with advanced AIDS. All 24 R5 isolates were inhibited by the CCR5-specific agents, PRO 140 and RANTES, while the two X4 viruses and the three R5X4 viruses were sensitive to the CXCR4-specific inhibitor, AMD3100. The five X4 or R5X4 viruses were all able to replicate in peripheral blood mononuclear cells that did not express CCR5. When tested using coreceptor-transfected cell lines, one R5 virus was also able to use CXCR6, and another R5X4 virus could use CCR3, BOB/GPR15, and CXCR6. The R5X4 and X4 viruses contained more-diverse V3 loop sequences, with a higher overall positive charge, than the R5 viruses. Hence, some HIV-1 subtype C viruses are able to use CCR5, CXCR4, or both CXCR4 and CCR5 for entry, and they are sensitive to specific inhibitors of entry via these coreceptors. These observations are relevant to understanding the rapid spread of HIV-1 subtype C in the developing world and to the design of intervention and treatment strategies.

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Balatif, Ridwan. "HIV Infection: What Should We Know?" Journal of Endocrinology, Tropical Medicine, and Infectiouse Disease (JETROMI) 2, no. 1 (February 1, 2020): 01–16. http://dx.doi.org/10.32734/jetromi.v2i1.2038.

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Acquired Immunodeficiency Syndrome (AIDS) was first known in 1981 in homosexual groups who had opportunistic infections and malignancies. In Indonesia the first AIDS case was reported in 1987 to a Dutch citizen living in the province of Bali. Cases of HIV infection in Indonesia are reported to increase every year and most occur at the age of 25-49 years. HIV transmission is not easily transmitted, even when an HIV-infected person takes antiretroviral drugs can reduce the risk of transmission by up to 96%. But one of the biggest challenges in managing HIV infection is facing stigma and discrimination. As many as 1 in 5 people living with HIV are afraid to come to the clinic because they will experience discrimination and stigma from the community if this condition occurs will cause treatment delay until PLWHA (People living with HIV/AIDS) will fall to the AIDS stage and PLWHA will be susceptible to opportunistic infections. A clinic in Namibia, when stigma and discrimination were successfully overcome, there was a 20% reduction in mortality in PLWHA

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Nora, Tamara, Charlotte Charpentier, Olivier Tenaillon, Claire Hoede, François Clavel, and Allan J. Hance. "Contribution of Recombination to the Evolution of Human Immunodeficiency Viruses Expressing Resistance to Antiretroviral Treatment." Journal of Virology 81, no. 14 (May 9, 2007): 7620–28. http://dx.doi.org/10.1128/jvi.00083-07.

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ABSTRACT Viral recombination has been postulated to play two roles in the development of human immunodeficiency virus (HIV) resistance to antiretroviral drugs. First, recombination has the capacity to associate resistance mutations expressed by distinct viruses, thereby contributing to the development of viruses with improved drug resistance. In addition, recombination could preserve diversity in regions outside those subject to strong selective pressure. In this study, we sought direct evidence for the occurrence of these processes in vivo by evaluating clonal virus populations obtained from the same patient before and after a treatment change that, while unsuccessful in controlling viral replication, led to the emergence of viruses expressing a different profile of resistance mutations. Phylogenetic studies supported the conclusion that the genotype arising after the treatment change resulted from the emergence of recombinant viruses carrying previously existing resistance mutations in novel combinations, whereas alternative explanations, including convergent evolution, were not consistent with observed genotypic changes. Despite evidence for a strong loss of genetic diversity in genomic regions coding for the protease and reverse transcriptase, diversity in regions coding for Gag and envelope was considerably higher, and recombination between the emerging viruses expressing the new pattern of resistance mutations and viral quasispecies in the previously dominant population contributed to this preservation of diversity in the envelope gene. These findings emphasize that recombination can participate in the adaptation of HIV to changing selective pressure, both by generating novel combinations of resistance mutations and by maintaining diversity in genomic regions outside those implicated in a selective sweep.

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Zennou, Véronique, Fabrizio Mammano, Sylvie Paulous, Dominique Mathez, and François Clavel. "Loss of Viral Fitness Associated with Multiple Gag and Gag-Pol Processing Defects in Human Immunodeficiency Virus Type 1 Variants Selected for Resistance to Protease Inhibitors In Vivo." Journal of Virology 72, no. 4 (April 1, 1998): 3300–3306. http://dx.doi.org/10.1128/jvi.72.4.3300-3306.1998.

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ABSTRACT We examined the viral replicative capacity and protease-mediated processing of Gag and Gag-Pol precursors of human immunodeficiency virus (HIV) variants selected for resistance to protease inhibitors. We compared recombinant viruses carrying plasma HIV RNA protease sequences obtained from five patients before protease inhibitor therapy and after virus escape from the treatment. Paired pretherapy-postresistance reconstructed viruses were evaluated for HIV infectivity in a quantitative single-cycle titration assay and in a lymphoid cell propagation assay. We found that all reconstructed resistant viruses had a reproducible decrease in their replicative capacity relative to their parental pretherapy counterparts. The extent of this loss of infectivity was pronounced for some viruses and more limited for others, irrespective of the inhibitor used and of the level of resistance. In resistant viruses, the efficiency of Gag and Gag-Pol precursor cleavage by the protease was impaired to different extents, as shown by the accumulation of several cleavage intermediates in purified particle preparations. We conclude that protease inhibitor-resistant HIV variants selected during therapy have an impaired replicative capacity related to multiple defects in the processing of Gag and Gag-Pol polyprotein precursors by the protease.

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Seth, Puja, Daniel Kidder, Sherri Pals, Julie Parent, Redempta Mbatia, Kipruto Chesang, Deogratius Mbilinyi, et al. "Psychosocial Functioning and Depressive Symptoms Among HIV-Positive Persons Receiving Care and Treatment in Kenya, Namibia, and Tanzania." Prevention Science 15, no. 3 (July 20, 2013): 318–28. http://dx.doi.org/10.1007/s11121-013-0420-8.

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Hussain, Syed Iqbal, Nandagopal Panneerselvam, Suniti Solomon, Sunil S. Solomon, Kaavya Adam, Ezhilarasi Chandrasekaran, David C. Montefiori, and Balakrishnan Pachamuthu. "Broadly Neutralizing Antibody Responses in a Subset of HIV-1-Infected Individuals in Chennai, India." Journal of the International Association of Providers of AIDS Care (JIAPAC) 16, no. 2 (July 7, 2016): 201–8. http://dx.doi.org/10.1177/1545109712467695.

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Identification of broadly neutralizing antibodies (NAbs) generated during the course of HIV-1 infection is essential for effective HIV-1 vaccine design. The magnitude and breadth of neutralizing activity in the sera from 46 antiretroviral treatment–naive HIV-1 clade C-infected individuals was measured in a single round infection assay using TZM-bl cells and multisubtype panel of env-pseudotyped viruses. Higher levels of NAb response (NAb titer 500 to >40 000) were measured in these patients against tier 1 and tier 2 viruses. The average magnitude of the NAb responses of chronically infected individuals against heterologous viruses was consistently higher than the response observed from individuals with long-term nonprogressor ( P = .086). To conclude, high titers of HIV-1 cross-neutralizing activity were observed in the sera from a subset of HIV-1-infected individuals in Chennai, India. Additional studies of the epitopes recognized by these antibodies may facilitate the discovery of an effective vaccine immunogen.

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Dorman, Nijsje, and Andrew Lever. "Comparison of Viral Genomic RNA Sorting Mechanisms in Human Immunodeficiency Virus Type 1 (HIV-1), HIV-2, and Moloney Murine Leukemia Virus." Journal of Virology 74, no. 23 (December 1, 2000): 11413–17. http://dx.doi.org/10.1128/jvi.74.23.11413-11417.2000.

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ABSTRACT Genomic RNA sorting between translation and packaging was examined for human immunodeficiency virus type 1 (HIV-1) and HIV-2 using actinomycin D and leptomycin B treatment. Both viruses behaved differently from a simple retrovirus under actinomycin D treatment. With leptomycin B, the lack of apparent functional separation between translation and packaging functions in lentiviruses was confirmed. HIV-2 RNA levels were more stable, but reverse transcriptase production declined similarly to HIV-1.

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Armani-Tourret, Marie, Zhicheng Zhou, Romain Gasser, Isabelle Staropoli, Vincent Cantaloube-Ferrieu, Yann Benureau, Javier Garcia-Perez, et al. "Mechanisms of HIV-1 evasion to the antiviral activity of chemokine CXCL12 indicate potential links with pathogenesis." PLOS Pathogens 17, no. 4 (April 19, 2021): e1009526. http://dx.doi.org/10.1371/journal.ppat.1009526.

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HIV-1 infects CD4 T lymphocytes (CD4TL) through binding the chemokine receptors CCR5 or CXCR4. CXCR4-using viruses are considered more pathogenic, linked to accelerated depletion of CD4TL and progression to AIDS. However, counterexamples to this paradigm are common, suggesting heterogeneity in the virulence of CXCR4-using viruses. Here, we investigated the role of the CXCR4 chemokine CXCL12 as a driving force behind virus virulence. In vitro, CXCL12 prevents HIV-1 from binding CXCR4 and entering CD4TL, but its role in HIV-1 transmission and propagation remains speculative. Through analysis of thirty envelope glycoproteins (Envs) from patients at different stages of infection, mostly treatment-naïve, we first interrogated whether sensitivity of viruses to inhibition by CXCL12 varies over time in infection. Results show that Envs resistant (RES) to CXCL12 are frequent in patients experiencing low CD4TL levels, most often late in infection, only rarely at the time of primary infection. Sensitivity assays to soluble CD4 or broadly neutralizing antibodies further showed that RES Envs adopt a more closed conformation with distinct antigenicity, compared to CXCL12-sensitive (SENS) Envs. At the level of the host cell, our results suggest that resistance is not due to improved fusion or binding to CD4, but owes to viruses using particular CXCR4 molecules weakly accessible to CXCL12. We finally asked whether the low CD4TL levels in patients are related to increased pathogenicity of RES viruses. Resistance actually provides viruses with an enhanced capacity to enter naive CD4TL when surrounded by CXCL12, which mirrors their situation in lymphoid organs, and to deplete bystander activated effector memory cells. Therefore, RES viruses seem more likely to deregulate CD4TL homeostasis. This work improves our understanding of the pathophysiology and the transmission of HIV-1 and suggests that RES viruses’ receptors could represent new therapeutic targets to help prevent CD4TL depletion in HIV+ patients on cART.

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Tremblay, Cécile L., Françoise Giguel, Christopher Kollmann, Yongbiao Guan, Ting-Chao Chou, Bahige M. Baroudy, and Martin S. Hirsch. "Anti-Human Immunodeficiency Virus Interactions of SCH-C (SCH 351125), a CCR5 Antagonist, with Other Antiretroviral Agents In Vitro." Antimicrobial Agents and Chemotherapy 46, no. 5 (May 2002): 1336–39. http://dx.doi.org/10.1128/aac.46.5.1336-1339.2002.

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ABSTRACT SCH-C (SCH 351125) is a small-molecule antagonist of the human immunodeficiency virus type 1(HIV-1) coreceptor CCR5. It has in vitro activity against R5 viruses with 50% inhibitory concentrations ranging from 1.0 to 30.9 nM. We have studied anti-HIV-1 interactions of SCH-C with other antiretroviral agents in vitro. Synergistic interactions were seen with nucleoside reverse transcriptase inhibitors (zidovudine and lamivudine), nonnucleoside reverse transcriptase inhibitors (efavirenz), and protease inhibitors (indinavir) at all inhibitory concentrations evaluated. We have also studied antiviral interactions between the HIV-1 fusion inhibitor T-20 and SCH-C against a panel of R5 HIV-1 isolates. We found synergistic interactions against all the viruses tested, some of which harbored resistance mutations to reverse transcriptase and protease inhibitors. Anti-HIV-1 synergy was also observed between SCH-C and another R5 virus inhibitor, aminooxypentane-RANTES. These findings suggest that SCH-C may be a useful anti-HIV drug in combination regimens and that a combination of chemokine coreceptor/fusion inhibitors may be useful in the treatment of multidrug-resistant viruses.

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Miura, Toshiyuki, Mark A. Brockman, Zabrina L. Brumme, Chanson J. Brumme, Florencia Pereyra, Alicja Trocha, Brian L. Block, et al. "HLA-Associated Alterations in Replication Capacity of Chimeric NL4-3 Viruses Carrying gag-protease from Elite Controllers of Human Immunodeficiency Virus Type 1." Journal of Virology 83, no. 1 (October 29, 2008): 140–49. http://dx.doi.org/10.1128/jvi.01471-08.

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ABSTRACT Human immunodeficiency virus type 1 (HIV-1)-infected persons who maintain plasma viral loads of <50 copies RNA/ml without treatment have been termed elite controllers (EC). Factors contributing to durable control of HIV in EC are unknown, but an HLA-dependent mechanism is suggested by overrepresentation of “protective” class I alleles, such as B*27, B*51, and B*57. Here we investigated the relative replication capacity of viruses (VRC) obtained from EC (n = 54) compared to those from chronic progressors (CP; n = 41) by constructing chimeric viruses using patient-derived gag-protease sequences amplified from plasma HIV RNA and inserted into an NL4-3 backbone. The chimeric viruses generated from EC displayed lower VRC than did viruses from CP (P < 0.0001). HLA-B*57 was associated with lower VRC (P = 0.0002) than were other alleles in both EC and CP groups. Chimeric viruses from B*57+ EC (n = 18) demonstrated lower VRC than did viruses from B*57+ CP (n = 8, P = 0.0245). Differences in VRC between EC and CP were also observed for viruses obtained from individuals expressing no described “protective” alleles (P = 0.0065). Intriguingly, two common HLA alleles, A*02 and B*07, were associated with higher VRC (P = 0.0140 and 0.0097, respectively), and there was no difference in VRC between EC and CP sharing these common HLA alleles. These findings indicate that cytotoxic T-lymphocyte (CTL) selection pressure on gag-protease alters VRC, and HIV-specific CTLs inducing escape mutations with fitness costs in this region may be important for strict viremia control in EC of HIV.

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Kageyama, Seiji, Alfredo Amolong Hinay, Elizabeth Freda Omengan Telan, Genesis May Jopson Samonte, Prisca Susan Agustin Leano, Akeno Tsuneki-Tokunaga, and Kyosuke Kanai. "Intrinsic Replication Competences of HIV Strains After Zidovudine/Lamivudine/Nevirapine Treatment in the Philippines." Journal of the International Association of Providers of AIDS Care (JIAPAC) 18 (January 1, 2019): 232595821985657. http://dx.doi.org/10.1177/2325958219856579.

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Although drug-resistant HIV variants are considered to be less fit than drug-susceptible viruses, replication competence of these variants harbored by patients has not yet been elucidated in detail. We herein assessed the replication competence of strains obtained from individuals receiving antiretroviral therapy. Among 11 306 participants in a drug resistance surveillance in the Philippines, 2629 plasma samples were obtained from individuals after a 12-month treatment with zidovudine (ZDV)/lamivudine (3TC)/nevirapine (NVP). The replication competence of HIV isolates was then assessed by reinoculation into seronegative peripheral blood mononuclear cells in the absence of drugs in vitro. The drug resistance rate was estimated to be 9.2%. Drug-resistant strains were still a minority of closely related strains in a phylogenetic cluster. Among the available 295 samples, 37 HIV strains were successfully isolated. Progeny viruses were produced at a wide range (5.1 × 106 to 3.4 × 109 copies/mL) in primary culture of peripheral blood mononuclear cells. The viral yields were higher than the corresponding plasma viral load (1300 to 3.4 × 106 copies/mL) but correlated with those ( r = 0.4). These results suggest that strains with higher intrinsic replication competence are one of the primary targets of newly selected drugs at the increasing phase of the plasma viral load during antiretroviral therapy.

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Rodes, Berta, Carmen De Mendoza, Mette Rodgers, Anthony Newell, Victoria Jimenez, Rosa Maria Lopez-Brugada, and Vincent Soriano. "Treatment Response and Drug Resistance in Patients Infected with HIV Type 1 Group O Viruses." AIDS Research and Human Retroviruses 21, no. 7 (July 2005): 602–7. http://dx.doi.org/10.1089/aid.2005.21.602.

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Quaranta, Maria Giovanna, Benedetta Mattioli, and Stefano Vella. "Glances in Immunology of HIV and HCV Infection." Advances in Virology 2012 (2012): 1–13. http://dx.doi.org/10.1155/2012/434036.

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Since the identification of HIV and HCV much progress has been made in the understanding of their life cycle and interaction with the host immune system. Despite these viruses markedly differ in their virological properties and in their pathogenesis, they share many common features in their immune escape and survival strategy. Both viruses have developed sophisticated ways to subvert and antagonize host innate and adaptive immune responses. In the last years, much effort has been done in the study of the AIDS pathogenesis and in the development of efficient treatment strategies, and a fatal infection has been transformed in a potentially chronic pathology. Much of this knowledge is now being transferred in the HCV research field, especially in the development of new drugs, although a big difference still remains between the outcome of the two infections, being HCV eradicable after treatment, whereas HIV eradication remains at present unachievable due to the establishment of reservoirs. In this review, we present current knowledge on innate and adaptive immune recognition and activation during HIV and HCV mono-infections and evasion strategies. We also discuss the genetic associations between components of the immune system, the course of infection, and the outcome of the therapies.

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Mulato, A. S., P. D. Lamy, M. D. Miller, W. X. Li, K. E. Anton, N. S. Hellmann, and J. M. Cherrington. "Genotypic and Phenotypic Characterization of Human Immunodeficiency Virus Type 1 Variants Isolated from AIDS Patients after Prolonged Adefovir Dipivoxil Therapy." Antimicrobial Agents and Chemotherapy 42, no. 7 (July 1, 1998): 1620–28. http://dx.doi.org/10.1128/aac.42.7.1620.

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ABSTRACT Adefovir dipivoxil [bis(pivaloyloxymethyl)-ester prodrug], an orally bioavailable prodrug of adefovir [9-(2-phosphonylmethoxyethyl)adenine], is currently in phase III clinical trials for the treatment of human immunodeficiency virus (HIV). In vitro experiments demonstrated that either a K65R or a K70E mutation in HIV reverse transcriptase (RT) was selected in the presence of adefovir, conferring a 16- or 9-fold decrease in susceptibility to adefovir, respectively. Previous data demonstrated that patients receiving adefovir dipivoxil monotherapy (125 mg daily) for 12 weeks experienced a median decrease in HIV RNA levels of 0.5 log10 copies/ml and that resistance to adefovir dipivoxil did not arise during that period. In the present investigation, a further study was undertaken to investigate whether RT mutations developed among viruses from patients who completed the 12-week study and who opted to enroll in a maintenance phase of prolonged (6- to 12-month) adefovir dipivoxil therapy (120 mg daily). Concomitant treatment with antiretroviral agents was permitted during the maintenance phase. The median decreases in HIV RNA levels for patients who completed 6 or 12 months of maintenance-phase dosing were 0.6 and 1.14 log10 copies/ml, respectively. The reductions in the HIV RNA levels were similar among patients who received adefovir dipivoxil with or without concomitant treatment with antiretroviral agents. Viruses from 8 of 29 patients dosed for up to 12 months developed RT mutations that were not present at baseline; these mutations may have been related to adefovir dipivoxil therapy. Viruses from two of the eight patients developed the K70E mutation while the patients were on therapy, but none of the viruses from patients developed the K65R RT substitution. Despite the development of RT mutations, sustained reductions (6 to 12 months) in viral load (≥0.7 log10 copies/ml decrease from baseline) were observed in all eight patients.

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Lewis, ME, B. Jubb, P. Simpson, A. Lopatukhin, D. Kireev, M. Bobkova, C. Craig, E. van der Ryst, M. Westby, and SL Butler. "Highly prevalent Russian HIV-1 V3-loop sequence variants are susceptible to maraviroc." Antiviral Chemistry and Chemotherapy 29 (January 2021): 204020662110251. http://dx.doi.org/10.1177/20402066211025156.

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Introduction Maraviroc inhibits CCR5-tropic HIV-1 across different subtypes in vitro and has demonstrated efficacy in clinical trials. V3-loop amino acid variants observed in individual maraviroc-resistant viruses have not been found to be predictive of reduced susceptibility. Sequence-database searches have demonstrated that approximately 7.3% of viruses naturally encode these variants, raising concerns regarding potential pre-existing resistance. A study from Russia reported that combinations of these same amino acids are present in the V3 loops of the Russian variant subtype A (IDU-A, now A6) with a much greater prevalence (range: 74.4%–92.3%) depending on the combination. However, these studies and database searches did not include phenotypic evaluation. Methods Sixteen Russian HIV-1 isolates (including sub-subtype A6 viruses) were assessed for V3 loop sequence and phenotypic susceptibility to maraviroc. Results All 12 of the A6 viruses and 2/4 subtype B isolates encoded V3-loop variants that have previously been identified in individual virus isolates with reduced susceptibility to maraviroc. However, despite the prevalence of these V3-loop amino acid variants among the tested viruses, phenotypic sensitivity to maraviroc was observed in all instances. Similarly, reduced susceptibility to maraviroc was not found in virus from participants who experienced virologic failure in a clinical study of maraviroc in Russia (A4001101, [NCT01275625]). Discussion Altogether, these data confirm that the presence of individual or combinations of V3-loop amino acid residues in sub-subtype A6 viruses alone does not predict natural resistance to maraviroc and that V3-loop genotype analysis of R5 virus prior to treatment is not helpful in predicting clinical outcome.

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Yusa, Keisuke, Wei Song, Matthias Bartelmann, and Shinji Harada. "Construction of a Human Immunodeficiency Virus Type 1 (HIV-1) Library Containing Random Combinations of Amino Acid Substitutions in the HIV-1 Protease due to Resistance by Protease Inhibitors." Journal of Virology 76, no. 6 (March 15, 2002): 3031–37. http://dx.doi.org/10.1128/jvi.76.6.3031-3037.2002.

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ABSTRACT Human immunodeficiency virus type 1 (HIV-1) heterogeneity contributes to the emergence of drug-resistant virus, escape from host defense systems, and/or conversion of the cellular tropism. To establish an in vitro system to address a heterogeneous virus population, we constructed a library of HIV-1 molecular clones containing a set of random combinations of zero to 11 amino acid substitutions associated with resistance to protease inhibitors by the HIV-1 protease. The complexity (2.1 × 105) of the HIV-1 library pNG-PRL was large enough to cover all of the possible combinations of zero to 11 amino acid substitutions (a total of 4,096 substitutions possible). The T-cell line MT-2 was infected with the HIV-1 library, and resistant viruses were selected after treatment by the protease inhibitor ritonavir (0.03 to 0.30 μM). The viruses that contained three to eight amino acid substitutions could be selected within 2 weeks. These results demonstrate that this HIV-1 library could serve as an alternative in vitro system to analyze the emergence of drug resistance and to evaluate the antiviral activity of novel compounds against multidrug-resistant viruses.

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Nijmeijer, Bernadien M., Catharina J. M. Langedijk, and Teunis B. H. Geijtenbeek. "Mucosal Dendritic Cell Subsets Control HIV-1’s Viral Fitness." Annual Review of Virology 7, no. 1 (September 29, 2020): 385–402. http://dx.doi.org/10.1146/annurev-virology-020520-025625.

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Dendritic cell (DC) subsets are abundantly present in genital and intestinal mucosal tissue and are among the first innate immune cells that encounter human immunodeficiency virus type 1 (HIV-1) after sexual contact. Although DCs have specific characteristics that greatly enhance HIV-1 transmission, it is becoming evident that most DC subsets also have virus restriction mechanisms that exert selective pressure on the viruses during sexual transmission. In this review we discuss the current concepts of the immediate events following viral exposure at genital mucosal sites that lead to selection of specific HIV-1 variants called transmitted founder (TF) viruses. We highlight the importance of the TF HIV-1 phenotype and the role of different DC subsets in establishing infection. Understanding the biology of HIV-1 transmission will contribute to the design of novel treatment strategies preventing HIV-1 dissemination.

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Khwaza, Vuyolwethu, Opeoluwa Oyedeji, and Blessing Aderibigbe. "Antiviral Activities of Oleanolic Acid and Its Analogues." Molecules 23, no. 9 (September 9, 2018): 2300. http://dx.doi.org/10.3390/molecules23092300.

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Viral diseases, such as human immune deficiency virus (HIV), influenza, hepatitis, and herpes, are the leading causes of human death in the world. The shortage of effective vaccines or therapeutics for the prevention and treatment of the numerous viral infections, and the great increase in the number of new drug-resistant viruses, indicate that there is a great need for the development of novel and potent antiviral drugs. Natural products are one of the most valuable sources for drug discovery. Most natural triterpenoids, such as oleanolic acid (OA), possess notable antiviral activity. Therefore, it is important to validate how plant isolates, such as OA and its analogues, can improve and produce potent drugs for the treatment of viral disease. This article reports a review of the analogues of oleanolic acid and their selected pathogenic antiviral activities, which include HIV, the influenza virus, hepatitis B and C viruses, and herpes viruses.

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Lanier, E. Randall, Roger G. Ptak, Bernhard M. Lampert, Laurie Keilholz, Tracy Hartman, Robert W. Buckheit, Marie K. Mankowski, Mark C. Osterling, Merrick R. Almond, and George R. Painter. "Development of Hexadecyloxypropyl Tenofovir (CMX157) for Treatment of Infection Caused by Wild-Type and Nucleoside/Nucleotide-Resistant HIV." Antimicrobial Agents and Chemotherapy 54, no. 7 (May 3, 2010): 2901–9. http://dx.doi.org/10.1128/aac.00068-10.

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ABSTRACT CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC50s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC50s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.

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Wildum, Steffen, Daniela Paulsen, Kai Thede, Helga Ruebsamen-Schaeff, and Holger Zimmermann. "In VitroandIn VivoActivities of AIC292, a Novel HIV-1 Nonnucleoside Reverse Transcriptase Inhibitor." Antimicrobial Agents and Chemotherapy 57, no. 11 (August 19, 2013): 5320–29. http://dx.doi.org/10.1128/aac.01377-13.

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ABSTRACTNonnucleoside reverse transcriptase inhibitors (NNRTIs) are important and frequently used elements of highly active antiretroviral therapy (HAART) for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. However, the development of drug resistance, as well as the side effects of existing drugs, defines a medical need for novel NNRTIs with excellent tolerability, improved activity against NNRTI-resistant viruses, and a low barrier to resistance. Within the chemical class of diarylpyrazole-[imidazolidinone]-carboxamides, AIC292 was identified as a promising novel HIV-1 NNRTI and has successfully completed single-dose clinical phase I studies. Here, we report on the antiviral activity of AIC292, evaluatedin vitroagainst wild-type and NNRTI-resistant HIV-1 isolates andin vivousing an engineered mouse xenograft model. AIC292 inhibited wild-type HIV-1 laboratory strains at low nanomolar concentrations, was well tolerated in different cell lines, and showed excellent selectivity in a lead profiling screen. In addition, activity of AIC292 could be demonstrated against a broad panel of wild-type HIV-1 group M and group O clinical isolates. AIC292 also retained activity against viruses harboring NNRTI resistance-associated mutations (RAMs), including the most prevalent variants, K103N, Y181C, and G190A. Interestingly, viruses bearing the L100I RAM were hypersusceptible to AIC292. Two-drug combination assays showed no antagonistic interactions between AIC292 and representative marketed HIV drugs with regard to antiviral activity. Furthermore, AIC292 displayed potent antiviralin vivoefficacy in a mouse xenograft model when applied once daily. Taken together, these data show that AIC292 represents a molecule with the antiviral properties of a novel NNRTI for the treatment of HIV-1 infection.

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Kibuule, Dan, Philomein Aiases, Nunurai Ruswa, Timothy William Rennie, Roger K. Verbeeck, Brian Godman, and Mwangana Mubita. "Predictors of loss to follow-up of tuberculosis cases under the DOTS programme in Namibia." ERJ Open Research 6, no. 1 (January 2020): 00030–2019. http://dx.doi.org/10.1183/23120541.00030-2019.

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BackgroundIn Namibia, one out of every 25 cases of tuberculosis (TB) is “lost to follow-up” (LTFU). This has impacted negatively on national efforts to end the disease by 2035. The aim of this study was to determine the trends and predictors of LTFU under the directly observed treatment short-course (DOTS) programme in Namibia.MethodsThe study involved a retrospective longitudinal analysis of a nationwide cohort of TB cases registered under the DOTS programme in Namibia from 2006 to 2015. The trends and predictors of LTFU among cases in the National Electronic TB Register of the National TB and Leprosy Program were respectively determined by interrupted time series and multivariate logistic regression analyses using R-Studio software.ResultsOut of 104 203 TB cases, 3775 (3.6%) were LTFU. A quarter (26%) of cases with poor outcomes were due to LTFU. The annual decline in cases of LTFU was significant between the first (2005–2010) and second (2010–2015) medium-term plan period for TB programme implementation (p=0.002). The independent predictors of LTFU were male sex (p=0.004), 15–24 years age group (p=0.03), provider of treatment (p<0.001), intensive phase (p=0.047) and living in border/transit regions (p<0.001). HIV co-infection and TB regimen were not significant predictors of LTFU.ConclusionsThere were declining trends in LTFU in Namibia. DOTS programmes should integrate socioeconomic interventions for young and middle-aged adult male TB cases to reduce LTFU.

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Bacheler, Lee, Susan Jeffrey, George Hanna, Richard D'Aquila, Lany Wallace, Kelly Logue, Beverly Cordova, et al. "Genotypic Correlates of Phenotypic Resistance to Efavirenz in Virus Isolates from Patients Failing Nonnucleoside Reverse Transcriptase Inhibitor Therapy." Journal of Virology 75, no. 11 (June 1, 2001): 4999–5008. http://dx.doi.org/10.1128/jvi.75.11.4999-5008.2001.

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ABSTRACT Efavirenz (also known as DMP 266 or SUSTIVA) is a potent nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) activity and of HIV-1 replication in vitro and in vivo. Most patients on efavirenz-containing regimens have sustained antiviral responses; however, rebounds in plasma viral load have been observed in some patients in association with the emergence of mutant strains of HIV-1. Virus isolates from the peripheral blood mononuclear cells (PBMCs) of patients with such treatment failures, as well as recombinant viruses incorporating viral sequences derived from patient plasma, show reduced in vitro susceptibility to efavirenz in association with mutations in the RT gene encoding K103N, Y188L, or G190S/E substitutions. Patterns of RT gene mutations and in vitro susceptibility were similar in plasma virus and in viruses isolated from PBMCs. Variant strains of HIV-1 constructed by site-directed mutagenesis confirmed the role of K103N, G190S, and Y188L substitutions in reduced susceptibility to efavirenz. Further, certain secondary mutations (V106I, V108I, Y181C, Y188H, P225H, and F227L) conferred little resistance to efavirenz as single mutations but enhanced the level of resistance of viruses carrying these mutations in combination with K103N or Y188L. Viruses with K103N or Y188L mutations, regardless of the initial selecting nonnucleoside RT inhibitor (NNRTI), exhibited cross-resistance to all of the presently available NNRTIs (efavirenz, nevirapine, and delavirdine). Some virus isolates from nevirapine or delavirdine treatment failures that lacked K103N or Y188L mutations remained susceptible to efavirenz in vitro, although the clinical significance of this finding is presently unclear.

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Tilton, John C., Craig B. Wilen, Chukwuka A. Didigu, Rohini Sinha, Jessamina E. Harrison, Caroline Agrawal-Gamse, Elizabeth A. Henning, et al. "A Maraviroc-Resistant HIV-1 with Narrow Cross-Resistance to Other CCR5 Antagonists Depends on both N-Terminal and Extracellular Loop Domains of Drug-Bound CCR5." Journal of Virology 84, no. 20 (August 11, 2010): 10863–76. http://dx.doi.org/10.1128/jvi.01109-10.

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ABSTRACT CCR5 antagonists inhibit HIV entry by binding to a coreceptor and inducing changes in the extracellular loops (ECLs) of CCR5. In this study, we analyzed viruses from 11 treatment-experienced patients who experienced virologic failure on treatment regimens containing the CCR5 antagonist maraviroc (MVC). Viruses from one patient developed high-level resistance to MVC during the course of treatment. Although resistance to one CCR5 antagonist is often associated with broad cross-resistance to other agents, these viruses remained sensitive to most other CCR5 antagonists, including vicriviroc and aplaviroc. MVC resistance was dependent upon mutations within the V3 loop of the viral envelope (Env) protein and was modulated by additional mutations in the V4 loop. Deep sequencing of pretreatment plasma viral RNA indicated that resistance appears to have occurred by evolution of drug-bound CCR5 use, despite the presence of viral sequences predictive of CXCR4 use. Envs obtained from this patient before and during MVC treatment were able to infect cells expressing very low CCR5 levels, indicating highly efficient use of a coreceptor. In contrast to previous reports in which CCR5 antagonist-resistant viruses interact predominantly with the N terminus of CCR5, these MVC-resistant Envs were also dependent upon the drug-modified ECLs of CCR5 for entry. Our results suggest a model of CCR5 cross-resistance whereby viruses that predominantly utilize the N terminus are broadly cross-resistant to multiple CCR5 antagonists, whereas viruses that require both the N terminus and antagonist-specific ECL changes demonstrate a narrow cross-resistance profile.

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Mazalovska, Milena, and J. Calvin Kouokam. "Lectins as Promising Therapeutics for the Prevention and Treatment of HIV and Other Potential Coinfections." BioMed Research International 2018 (2018): 1–12. http://dx.doi.org/10.1155/2018/3750646.

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Human immunodeficiency virus-acquired immunodeficiency syndrome (HIV/AIDS) remains a global health problem. Current therapeutics specifically target the viral pathogen at various stages of its life cycle, although complex interactions between HIV and other pathogenic organisms are evident. Targeting HIV and concomitant infectious pathogens simultaneously, both by therapeutic regimens and in prevention strategies, would help contain the AIDS pandemic. Lectins, a ubiquitous group of proteins that specifically bind glycosylated molecules, are interesting compounds that could be used for this purpose, with demonstrated anti-HIV properties. In addition, potential coinfecting pathogens, including other enveloped viruses, bacteria, yeasts and fungi, and protozoa, display sugar-coated macromolecules on their surfaces, making them potential targets of lectins. This review summarizes the currently available findings suggesting that lectins should be further developed to simultaneously fight the AIDS pandemic and concomitant infections in HIV infected individuals.

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45

Zhang, Haili, Yan Zhou, Cecily Alcock, Tara Kiefer, Daphne Monie, Janet Siliciano, Quan Li, et al. "Novel Single-Cell-Level Phenotypic Assay for Residual Drug Susceptibility and Reduced Replication Capacity of Drug-Resistant Human Immunodeficiency Virus Type 1." Journal of Virology 78, no. 4 (February 15, 2004): 1718–29. http://dx.doi.org/10.1128/jvi.78.4.1718-1729.2004.

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ABSTRACT Human immunodeficiency virus type 1 (HIV-1)-infected individuals who develop drug-resistant virus during antiretroviral therapy may derive benefit from continued treatment for two reasons. First, drug-resistant viruses can retain partial susceptibility to the drug combination. Second, therapy selects for drug-resistant viruses that may have reduced replication capacities relative to archived, drug-sensitive viruses. We developed a novel single-cell-level phenotypic assay that allows these two effects to be distinguished and compared quantitatively. Patient-derived gag-pol sequences were cloned into an HIV-1 reporter virus that expresses an endoplasmic reticulum-retained Env-green fluorescent protein fusion. Flow cytometric analysis of single-round infections allowed a quantitative analysis of viral replication over a 4-log dynamic range. The assay faithfully reproduced known in vivo drug interactions occurring at the level of target cells. Simultaneous analysis of single-round infections by wild-type and resistant viruses in the presence and absence of the relevant drug combination divided the benefit of continued nonsuppressive treatment into two additive components, residual virus susceptibility to the drug combination and selection for drug-resistant variants with diminished replication capacities. In some patients with drug resistance, the dominant circulating viruses retained significant susceptibility to the combination. However, in other cases, the dominant drug-resistant viruses showed no residual susceptibility to the combination but had a reduced replication capacity relative to the wild-type virus. In this case, simplification of the regimen might still allow adequate suppression of the wild-type virus. In a third pattern, the resistant viruses had no residual susceptibility to the relevant drug regimen but nevertheless had a replication capacity equivalent to that of wild-type virus. In such cases, there is no benefit to continued treatment. Thus, the ability to simultaneously analyze residual susceptibility and reduced replication capacity of drug-resistant viruses may provide a basis for rational therapeutic decisions in the setting of treatment failure.

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Ziermann, Rainer, Kay Limoli, Kalyan Das, Edward Arnold, Christos J. Petropoulos, and Neil T. Parkin. "A Mutation in Human Immunodeficiency Virus Type 1 Protease, N88S, That Causes In Vitro Hypersensitivity to Amprenavir." Journal of Virology 74, no. 9 (May 1, 2000): 4414–19. http://dx.doi.org/10.1128/jvi.74.9.4414-4419.2000.

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ABSTRACT Amprenavir (Agenerase, 141-W94, VX-478) is a human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PRI) recently approved for the treatment of HIV-1 infection in the United States. A major cause of treatment failure is the development of resistance to PRIs. One potential use for amprenavir is as salvage therapy for patients for whom treatment that includes one (or more) of the other four currently approved PRIs—saquinavir, indinavir, ritonavir, and nelfinavir—has failed. We evaluated the cross-resistance to amprenavir of viruses that evolved during treatment with the two most commonly prescribed PRIs, nelfinavir and indinavir. Unexpectedly, a dramatic increase in susceptibility (2.5- to 12.5-fold) was observed with 20 of 312 (6.4%) patient viruses analyzed. The most pronounced increases in susceptibility were strongly associated with an N88S mutation in protease. All viruses that carried the N88S mutation were hypersensitive to amprenavir. Site-directed mutagenesis studies confirmed the causal role of N88S in determining amprenavir hypersensitivity. The presence of the N88S mutation and associated amprenavir hypersensitivity may be useful in predicting an improved clinical response to amprenavir salvage therapy.

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Repits, Johanna, Monica Öberg, Joakim Esbjörnsson, Patrik Medstrand, Anders Karlsson, Jan Albert, Eva Maria Fenyö, and Marianne Jansson. "Selection of human immunodeficiency virus type 1 R5 variants with augmented replicative capacity and reduced sensitivity to entry inhibitors during severe immunodeficiency." Journal of General Virology 86, no. 10 (October 1, 2005): 2859–69. http://dx.doi.org/10.1099/vir.0.81111-0.

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Early in human immunodeficiency virus 1 (HIV-1) infection CCR5-using (R5) viruses predominate. With disease progression, approximately 50 % of infected individuals develop viruses able to use CXCR4. In the present work, the evolution of the biological properties of HIV-1 was studied in patients who retain viruses with an R5 phenotype despite AIDS onset. A panel of primary R5 HIV-1 isolates sequentially obtained at an asymptomatic stage and after AIDS diagnosis was examined. The viruses were selected based on our previous observation that R5 variants with reduced sensitivity to RANTES inhibition may appear during disease progression. Biological properties of the early and late R5 viruses, including infectivity, replicative capacity, impact of cationic polymer and sensitivity to inhibition by the entry inhibitors T-20 and TAK-779, were evaluated. R5 viruses isolated after AIDS onset displayed elevated replicative capacity and infectivity, and did not benefit from cationic polymer assistance during infection. Late R5 isolates also exhibited reduced sensitivity to inhibition by T-20 and TAK-779, even though the included patients were naïve to treatment with entry inhibitors and the isolates had not acquired mutations within the gp41 HR1 region. In addition, CD4+ T-cell counts at the time of R5 virus isolation correlated with infectivity, replicative capacity and sensitivity to inhibition by entry inhibitors. The results indicate that R5 HIV-1 variants with augmented replicative capacity and reduced sensitivity to entry inhibitors may be selected for during severe immunodeficiency. At a time when the clinical use of entry inhibitors is increasing, this observation could be of importance in the optimal design of such treatments.

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Roy, Jocelyn, Jean-Sébastien Paquette, Jean-François Fortin, and Michel J. Tremblay. "The Immunosuppressant Rapamycin Represses Human Immunodeficiency Virus Type 1 Replication." Antimicrobial Agents and Chemotherapy 46, no. 11 (November 2002): 3447–55. http://dx.doi.org/10.1128/aac.46.11.3447-3455.2002.

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ABSTRACT The immunosuppressive macrolide rapamycin is used in humans to prevent graft rejection. This drug acts by selectively repressing the translation of proteins that are encoded by an mRNA bearing a 5′-polypyrimidine tract (e.g., ribosomal proteins, elongation factors). The human immunodeficiency virus type 1 (HIV-1) carries a polypyrimidine motif that is located within the tat exon 2. Treatment of human T lymphoid cells with rapamycin resulted in a marked diminution of HIV-1 transcription when infection was performed with luciferase reporter T-tropic and macrophage-tropic viruses. Replication of fully infectious HIV-1 particles was abolished by rapamycin treatment. The rapamycin-mediated inhibitory effect on HIV-1 production was reversed by FK506. The anti-HIV-1 effect of rapamycin was also seen in primary human cells (i.e., peripheral blood lymphocytes) from different healthy donors. Rapamycin was shown to diminish basal HIV-1 long terminal repeat gene expression, and the observed effect of rapamycin on HIV-1 replication seems to be independent of the virus-specific transactivating Tat protein. A constitutive β-actin promoter-based reporter gene vector was unaffected by rapamycin treatment. Kinetic virus infection studies and exposure to reporter viruses pseudotyped with heterologous envelope proteins (i.e., amphotropic murine leukemia virus and vesicular stomatitis virus G) suggested that rapamycin is primarily affecting the life cycle of HIV-1 at a transcriptional level. Northern blot analysis confirmed that this compound is selectively targeting HIV-1 mRNA synthesis.

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Bull, Marta E., Gerald H. Learn, Scott McElhone, Jane Hitti, David Lockhart, Sarah Holte, Joan Dragavon, Robert W. Coombs, James I. Mullins, and Lisa M. Frenkel. "Monotypic Human Immunodeficiency Virus Type 1 Genotypes across the Uterine Cervix and in Blood Suggest Proliferation of Cells with Provirus." Journal of Virology 83, no. 12 (April 1, 2009): 6020–28. http://dx.doi.org/10.1128/jvi.02664-08.

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ABSTRACT Understanding the dynamics and spread of human immunodeficiency virus type 1 (HIV-1) within the body, including within the female genital tract with its central role in heterosexual and peripartum transmission, has important implications for treatment and vaccine development. To study HIV-1 populations within tissues, we compared viruses from across the cervix to those in peripheral blood mononuclear cells (PBMC) during effective and failing antiretroviral therapy (ART) and in patients not receiving ART. Single-genome sequences of the C2-V5 region of HIV-1 env were derived from PBMC and three cervical biopsies per subject. Maximum-likelihood phylogenies were evaluated for differences in genetic diversity and compartmentalization within and between cervical biopsies and PBMC. All subjects had one or more clades with genetically identical HIV-1 env sequences derived from single-genome sequencing. These sequences were from noncontiguous cervical biopsies or from the cervix and circulating PBMC in seven of eight subjects. Compartmentalization of virus between genital tract and blood was observed by statistical methods and tree topologies in six of eight subjects, and potential genital lineages were observed in two of eight subjects. The detection of monotypic sequences across the cervix and blood, especially during effective ART, suggests that cells with provirus undergo clonal expansion. Compartmentalization of viruses within the cervix appears in part due to viruses homing to and/or expanding within the cervix and is rarely due to unique viruses evolving within the genital tract. Further studies are warranted to investigate mechanisms producing monotypic viruses across tissues and, importantly, to determine whether the proliferation of cells with provirus sustain HIV-1 persistence in spite of effective ART.

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Raugi, Dana N., Robert A. Smith, Selly Ba, Macoumba Toure, Fatou Traore, Fatima Sall, Charlotte Pan, et al. "Complex Patterns of Protease Inhibitor Resistance among Antiretroviral Treatment-Experienced HIV-2 Patients from Senegal: Implications for Second-Line Therapy." Antimicrobial Agents and Chemotherapy 57, no. 6 (April 9, 2013): 2751–60. http://dx.doi.org/10.1128/aac.00405-13.

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ABSTRACTProtease inhibitor (PI)-based antiretroviral therapy (ART) can effectively suppress HIV-2 plasma load and increase CD4 counts; however, not all PIs are equally active against HIV-2, and few data exist to support second-line therapy decisions. To identify therapeutic options for HIV-2 patients failing ART, we evaluated the frequency of PI resistance-associated amino acid changes in HIV-2 sequences from a cohort of 43 Senegalese individuals receiving unboosted indinavir (n= 18 subjects)-, lopinavir/ritonavir (n= 4)-, or indinavir and then lopinavir/ritonavir (n= 21)-containing ART. Common protease substitutions included V10I, V47A, I54M, V71I, I82F, I84V, L90M, and L99F, and most patients harbored viruses containing multiple changes. Based on genotypic data, we constructed a panel of 15 site-directed mutants of HIV-2ROD9containing single- or multiple-treatment-associated amino acid changes in the protease-encoding region ofpol. We then quantified the susceptibilities of the mutants to the HIV-2 “active” PIs saquinavir, lopinavir, and darunavir using a single-cycle assay. Relative to wild-type HIV-2, the V47A mutant was resistant to lopinavir (6.3-fold increase in the mean 50% effective concentration [EC50]), the I54M variant was resistant to darunavir and lopinavir (6.2- and 2.7-fold increases, respectively), and the L90M mutant was resistant to saquinavir (3.6-fold increase). In addition, the triple mutant that included I54M plus I84V plus L90M was resistant to all three PIs (31-, 10-, and 3.8-fold increases in the mean EC50for darunavir, saquinavir, and lopinavir, respectively). Taken together, our data demonstrate that PI-treated HIV-2 patients frequently harbor viruses that exhibit complex patterns of PI cross-resistance. These findings suggest that sequential PI-based regimens for HIV-2 treatment may be ineffective.

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Journal articles on the topic 'HIV (Viruses) – Treatment – Namibia'

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